4-trifluoromethyl-anthranilic acids

ABSTRACT

5-Sulfamyl-4-trifluoromethyl-anthranilic acids of the formula I esters and salts thereof, particularly the N-furfuryl-4trifluoromethyl-5-sulfamyl-anthranilic acid, exhibit diuretic effects.

United States Patent Werner et a1.

[54] 4-TRIFLUOROMETHYL-ANTHRANILIC ACIDS [72] Inventors: Lincoln HarveyWerner, 94 Larned Road;

George De Stevens, 2 Warwick Road, Woodland Park, both of Summit. NJ.

[22] Filed: April 27, 1967 [21] Appl. No.: 634,101

I Related US. Application Data [63] Continuation-impart of Ser. No.606,599, Jan. 3, 1967, which is a continuation-in-part of Ser. No.553,703, May 31, 1966, abandoned, which is a continuation-in-part ofSer. No. 508,556, Nov. 18,1965.

[S2] U.S. Cl ..260/239.6, 260/397.7, 260/239.65,

260/556, 260/332.2, 260/347.2, 260/295, 260/307, 260/305, 260/309.2,260/326.12, 260/247.1, 260/287, 260/326.82, 260/268, 260/329, 260/465,424/228, 424/229, 424/285, 424/321 [51] Int. Cl. C07d 5/14 [58] Field ofSearch ..260/239.6239.95, 260/397.7, 556, 515, 518, 558 X, 558 H, 430

[56] References Cited UNITED STATES PATENTS 3,072,656 H1 963 Werner eta1. ..260/397.7 3,058,882 10/1962 Sturm et al. 3,009,910 11/1961 Ziegler2,910,488 10/1959 Novello .I260/391I7 [151 3,678,039 14 1 July 18,1972

FOREIGN PATENTS OR APPLICATIONS 1,122,541 8/1962 Germany ..260/397.7

OTHER PUBLICATIONS Sturm et al., Ben, Vol. 99, pp. 328 343 1 1966)QDID4Yule et al.,J. Med. Chem, vol. 1 pp. 121-133(1959)RS1.15 .Iucker et al.,Arzneimi Telforschung, vol. 13, pp. 269- 280 (1963) PrimaryExaminerHenry R. .liles Assistant Examiner-Harry I. Moatz Attorney-HarryGoldsmith, Joseph G. Kolodny and Bryant W. Brennan R =aliphatic oraraliphatic hydrocarbon radical 01 at 11 H, aliphatic or araliphatichydrocarbon or acyl esilse 9E r H esters and salts thereof, particularlythe N-furfuryl-4- trifluoromethyl-S-sulfamyl-anthranilic acid, exhibitdiuretic effects.

9 Claims, No Drawings 4-TRlFLUOROMETI-IYL-ANTIIRANILIC ACIDSCROSS-REFERENCES TO RELATED APPLICATIONS This is continuation-in-part ofapplication Ser. No. 606,599, 5 filed Jan. 3, 1967, which in turn is acontinuation-in-part of application Ser. No. 553,703, filed May 31,1966, now abandoned, which in turn is a continuation-in-part ofapplication Ser. No. 508,556, filed Nov. 18, 1965.

SUMMARY OF THE INVENTION The present invention concerns and has for itsobject the provision of new 5-sulfamyl-4-trifluoromethyl-anthranilicacids and their acid derivatives, more particularly those of formula l,in which R stands for an aliphatic or araliphatic hydrocarbon or an arylradical, each of R and R for hydrogen, an aliphatic or araliphatichydrocarbon or acyl radcial or for an aryl radical, esters thereof andsalts of these compounds, as well as corresponding pharmaceuticalcompositions, new starting materials and methods for the preparation ofthe new compounds. Said compositions are useful as orally applicablediuretic and natriuretic agents in order to relieve excessive waterand/or salt retention, for example in connection with heart and kidneydiseases, as well as in the adjunctive management of hypertension.

DESCRIPTION OF THE PREFERRED EMBODIMENTS The aliphatic or araliphatichydrocarbon radicals mentioned above may be interrupted by, and the arylradicals may contain, hetero atoms, such as nitrogen, oxygen and/orsulfur atoms. Aliphatic radicals are, for example, lower alkyl, such asmethyl, ethyl, nor i-propyl, -butyl, -pentyl, -hexyl or -heptyl, loweralkenyl, such as vinyl, ally], methallyl, Z-butenyl or 3-methyl-Z-butenyl, lower alkynyl, such as propargyl, cycloalkyl,cycloalkenyl, cycloalkyl-lower alkyl or cycloalkenyllower alkyl whichmay be monoor bicyclic and have preferably three to seven ring-carbonand one to four chaincarbon atoms, such as cyclopropyl,2,3-dimethyl-cyclopropyl, cyclobutyl, cyclopentyl, 2- or3-methyl-cyclopentyl, 2,5- or 3,4-dimethyl-cyclopentyl, cyclohexyl, 2-,3- or 4-methylcyclohexyl, 2,3-, 2,4- or 3,4-dimethyl-cyclohexyl, 2,4,6-trimethyl-cyclohexyl, cycloheptyl, cyclooctyl, 2- or 7-norbornanyl, lorZ-decahydronaphthyl and the corresponding cycloalkyl-lower alkyl groups,in which the the chain especially represents methyl, but also ethyl,propyl, straight or branched butyl, and contains in any of the positionsavailable for substitution one of the specific cycloalkyl groups listedabove. A cycloalkenyl or cycloalkenyl-lower alkyl group represents, forexample, I- or 2-cyclopentenyl, 2,4-cyclopentadienyl, 2- or3methyl-2-cyclopentenyl, 4,5-dimethyl-2- cyclopentenyl, l-, 2- or3-cyclohexenyl, 2,5-cyclohexadienyl, 2-, 3- or 4-methyl-lor2-cyclohexenyl, 2,4- or 3,5- dimethyllor 2-cyclohexenyl, 2,4,6l-, 2- or3-cycloheptenyl), 2,6- cycloheptadienyl, 2-cyclooctenyl or2-norborn-5-enyl and the corresponding cycloalkenyl-lower alkyl groupsin which the chain has the previously-given meaning and contains in anyof the positions available for substitution one of the specificcycloalkenyl groups listed above. R and R when taken together, may alsorepresent lower alkylene or alkenylene, such as ethylene, l,3-propylene,l,4-butylene, 1,4-or l,5-pentylene, l,5-, 2,5- or 1,6-hexylene or2,6-heptylene; l,4-but-2- enylene, 1,4- or l,5-pent-2-enylene,l,5-hex-2-enylene, 1,6- hex-3-enylene or 2,6-hept-3-enylene. Anaraliphatic hydrocarbon or an aryl radical preferably stands for monoorbicyclic carbocyclic or heterocyclic, especially mono-aza, oxaorthiacyclic, aryl-lower alkyl, aryl-lower alkenyl or aryl, in which thelower alkyl or alkenyl moiety preferably has only up to fourchain-carbon atoms, such as benzyl, lor 2-phenylethyl, l-, 2- or3-phenyl-propyl, 2-phenyl-2-propyl, l-, 2-, 3- or 4-phenyl butyl, lor2-phenyl-2-butyl; styryl or cinnamyl, and the corresponding heterocyclicaralkyl, aralkenyl or aryl radicals in which aryl is, for example, 2, 3-or 4pyridyl, 2- or 3-furyl or -thienyl, 5-( l,2-oxazolyl), 2-(1,3-oxazolyl), 2-( 1,3- 75 thiazolyl) or 2-benzimidazolyl. Araliphatichydrocarbon radicals are also partially hydrogenated, preferably biortricyclic aryl radicals, bound at the aliphatic portion, such as lor2-indolinyl, lor 2-( l,2,3,4-thtrahydronaphthyl) or 9-fluorenyl. Ahydrocarbon radical that is interrupted by hetero atoms is, for example,lower aza-, oxa or thia-alkylene (representing R, and R such as 3-aza-,3-oxaor 3-thia-pentylene-( l ,5 3-methyl or ethyl-3-aza-pentylene-(1,5), 3-aza-hexylene-( 1,6) or 4-azaor oxaheptylene-( 2,5), furthermoresec. or tert. amino-lower alkyl, such as monoor di-loweralkylamino-lower alkyl, lower alkyIene-imino-lower alkyl, lower aza-,oxaor thia-alkyleneimino-lower alkyl, e.g. 2-ethylaminoethyl, 2-dimethylamino-ethyl, 3-diethylamino-propyl, 2-pyrrolidinoethyl,Z-piperidino-ethyl, 2-(4-methyl-piperazino)ethyl or 2- morpholino-ethyl,or lower alkoxyor alkylmercapto-lower alkyl, such as 2ethoxyethyl or-propyl, 3-methoxy-propyl or 2- ethylmercapto-ethyl.

These radicals may be unsubstituted or substituted, especially in thearomatic portion, by one or more than one of the same or of differentsubstituents, for example, lower alkyl groups, such as those mentionedabove, free or functionally converted hydroxy or mercapto groups, suchas lower alkoxy or alkylmercapto, halogen, e.g. fluoro, chloro or bromo,trifluoromethyl, nitro, amino, especailly di-lower alkylamino, e.g.dimethylamino or diethylamino, sulfamyl, carbamyl or cyano. Suchsubstituted aliphatic radicals are, for example, lower haloalkyl, e.g.2-chloro-, bromoor iodo-ethyl, 2,2- difluoroor dichloro-ethyl,3,3,3-trifluoro or trichloro-ethyl, 2- a or 3-fluoroor chloro-propyl or2,2-dichloropropyl, halogenated lower alkoxyor alkylmercapto-loweralkyl, such as 2-(2-chloroethoxy)-ethyl, 2-(2,2-dichloroethoxy(-ethyl,2- (2,2,ltrifluoroethylmercapto)-ethyl or2-(2,2-dichloroethylmercapto)-ethyl, carbamyl-lower alkyl, such ascarbamyl- 5 methyl, N,N-dimethylcarbamyl-methyl, Z-carbamyl-ethyl or2-N,N-diethylcarbamyl-ethyl. In the compounds containing the abovealiphatic radicals, two hetero atoms are separated by at least twocarbon atoms. Preferred substituted aryl moieties are (loweralkyl)-phenyl, (lower alkoxy)-phenyl, (lower alkylmercapto)-phenyl,(halogeno)-phenyl, (trifluoromethyl)-phenyl, (di-loweralkylamino)-phenyl, (lower alkyl)-furyl or (lower alkyl)-thienyl.

An acyl radical preferably stands for lower alkanoyl, such as acetyl,propionyl, butyryl or pivalyl, but also for lower alkenoyl, such asacryloyl or methacryloyl, monocyclic carbocyclic aroyl or aryl-loweralkanoyl or alkenoyl, such as benzoyl, phenylacetyl or connamoyl. Theseacyl radicals may be unsubstituted or substituted as shown for the abovehydrocarbon radicals.

Esters of the compounds of Formula I are particularly those of loweralkanols, such as methanol, ethanol, lor 2-propanol, l-, 2- or tert.butanol, or of monocyclic carbocyclic aryl-lower alkanols, such asbenzyl alcohol or Z-phenyl-ethanol.

The compounds of the invention exhibit valuable pharmacologicalproperties. Apart from hypotensive effects, they show primarily diureticactivity, as can be demonstrated in animal tests using, for examplemammals, e.g. rats or dogs,as test objects. Besides their abovementioned utility, the compounds of the invention are also usefulintermediates in the preparation of other valuable products primarily ofpharmacologically active compounds.

Particularly useful are the compounds of Formula II in which R, standsfor lower alkyl, lower alkenyl, cycloalkyl, cycloalkenyl,cycloalkyl-alkyl or cycloalkenyl-alkyl with five to seven ring-carbonand one to four chain-carbon atoms,

monocyclic carbocyclic or monoaza-, oxaor thiacyclic arylalkyl with oneto four chain-carbon atoms, lower fluoroor chloroalkyl, lower alkoxyoralkylmercapto-lower alkyl, lower fluoroor chloroalkoxyor-alkylmercapto-lower alkyl, di-lower alkylaminoor loweralkyleneimino-lower alkyl, R, for hydrogen, lower alkyl or loweralkanoyl and R for hydrogen, lower alkyl, cycloalkyl, cycloalkenyl,cycloalkylalkyl or cycloalkenyl-alkyl with five to seven ring-carbon andone to four chain-carbon atoms, monocyclic carbocyclic or monoaza-,oxaor thia-cyclic aryl or aryl-alkyl with one to four chain-carbonatoms, wherein two hetero atoms in the aliphatically substitutedcompounds are separated by at least two carbon atoms and carbocyclicaryl is unsubstituted or substituted by lower alkyl, lower alkoxy, loweralkylmercapto, halogeno, trifluoromethyl or di-lower alkylamino andheterocyclic aryl is unsubstituted or substituted by lower alkyl, andalkali metal, alkaline earth metal or ammonium salts thereof.

Especially valuable are the compounds of Formula II in which R standsfor benzyl, lor Z-phenyl-ethyl, furfuryl or thenyl, R for hydrogen,benzyl or alkanoyl with one to four carbon atoms and R for hydrogen,methyl, phenyl, benzyl, lor 2-phenylethyl, furfuryl or thenyl, andalkali metal, alkaline earth metal or ammonium salts thereof, which whengiven to rats at oral doses between about 25 and l mg/kg/day, or to dogsat oral doses between about and 50 mg/kg/day, show outstanding diureticactivity.

The compounds of the invention are prepared according to methods inthemselves known. Advantageously they are obtained by a. reacting acompound of the Formula lll III or an ester, halide, amide or hydrazidethereof, with that ofthe formula R NH and hydrolyzing any resultingamide or hydrazide and/or if desired, converting any resulting compoundinto another disclosed compound.

Any ester used as starting material may be such as described above forthe final products. The amides or hydrazides used as starting materialsmay be N-substituted or N-unsubstituted, for example, by one or morethan one aliphatic, araliphatic or aromatic radical, e.g. any of thosedescribed above.

The above process is carried out according to standard methods, in thepresence or absence of diluents, preferably such as are inert to thereagents and are solvents thereof, of catalysts, condensing agentsand/or inert atmospheres, at low temperatures, room temperature oradvantageously elevated temperatures, at atmospheric or superatmosphericpressure.

In the above reaction the amine reagent is advantageously used inexcess, in order to neutralize the generated acid. It may, however, alsobe used in equivalent amounts and in the presence of other condensingagents such as inorganic or organic bases, e.g. alkali metal carbonatesor bicarbonates or tertiary nitrogen bases, for example, tri-loweralkylamines, N,N-dimethylaniline or pyridine.

Any resulting amide or hydrazide is hydrolyzed in the usual manner, forexample, with the use of an alkali, e.g. aqueous alkali or alkalineearth metal hydroxides, or quaternary ammonium hydroxides. The compoundsof the invention so obtained may be converted into each other accordingto known methods. For example, resulting compounds in which R stands forhydrogen may be reacted with a reactive ester of a correspondingalcohol, for example, that of a hydrohalic or sulfonic acid, or may beacylated, for example, with a reactive functional derivative of acorresponding acid, such as a halide or anhydride thereof, or resultingacyl derivatives may be hydrolyzed, for example with the use of acidicor alkaline hydrolyzing agents. Resulting esters may be hydrolyzed ortransesterified or resulting acids esterified in known manner.

The compounds of the invention are obtained in the free form or in theform of their salts, depending on the conditions under which the processis carried out, the salts are also included in the present invention.These are particularly derived from the free acids and therapeuticallyuseful inorganic of organic bases, primarily the alkali metal, alkalineearth metal, e.g. sodium, potassium, magnesium or calcium salts, orammonium salts derived from ammonia or amines, such as thosecorresponding to the amino group e.g. mono-, dior tri-lower alkylamines,-cycloalkylamines, cycloalkyl-lower alkylamines, or -aralkylamines,mixed amines or quaternary nitrogen bases, such as pyridine, collidineor lutidine.

The invention further includes any variant of the present process inwhich an intermediate product obtainable at any stage of the process isused as starting material and any remaining steps are carried out, orthe process is discontinued at any stage thereof, or in which thestarting materials are formed under the reaction conditions, or in whichthe reaction components are used in the form of their salts. Forexample, in case the amine R -NH-R is identical with R Nl-l,, it may bereacted in a single step with a 2-halo- 4-trifluoromethyl-5-halosulfonyl-benzoic acid or a functional derivative thereof, wherebycompounds of the Formula II] or derivatives thereof, are formed underthe reaction conditions. Mainly, those starting materials should be usedin the reactions of the invention that lead to the formation of thosecompounds indicated above as being especially valuable.

The starting material is new, but can be prepared according to knownmethods. For example, 3-(fluoro or chloro)-4- bromo-benzotrifluoride or3-(fluor, chloro or bromo)-4-iodobenzotrifluoride is converted into a4-metal compound, e.g. a Grignard compound, which is then carbonated inorder to yield the 2-(fluor, chloro or bromo)-4-trifluoromethyl-benzoicacid. The latter, or an acid derivative thereof, is eitherhalosulfonated or reacted with the amine R NH-R to yield thecorresponding 5-halosulfonyl-compounds, anthranilic acids or theirderivatives respectively. The former can be reacted with the compound RHN in order to obtain a compound of Formula ill or a derivative thereof,and the latter, or a corresponding N-acyl derivative thereof, can behalo-sulfonated to yield a compound of Formula IV or a derivativethereof. Another method for the preparation of the starting material ofFormula III consists in halosulfonating a3-amino-4-halobenzotrifluoride, convening the resulting 5-halo-2-trifluoromethyl-sulfanilic acid in its halide and reacting the latterwith the compound R NH, in order to obtain a corresponding5-halo-2-trifluoromethyl-sulfanilamide. This is reacted with cuprouscyanide to yield the corresponding 5-sulfamyl-4-trifluoromethyl-anthranilic acid nitrile, which can behydrolized in conventional manner. The resulting anthranilic acid or itsamide is then converted into the diazonium salt, which according to theSandmeyer reaction yields the desired starting material. Theintermediary N-unsubstituted 5- sulfamyl-4-trifluoromethyl-anthranilicacid may also be obtained by potassium permanganate oxidation of a4-sulfamyl- S-trifluoromethyl-o-toluidine. Also most of theintermediates in said synthesis, starting from the2-halo-4-trifluoromethylbenzoic acids and the derivatives thereof, arenew and are further an object of the present invention.

Particularly useful are the intermediates of Formula III in which Xstands for fluoro or chloro and R for hydrogen, especially the amide,monoor di-lower alkyl or aralkylamindes, the hydrazide, monoorN,N'-di-lower alkyl or aralkylhydrazides thereof, which show primarilyhypotensive effects, as can be demonstrated in animal test using, forexample mammals, e.g. dogs, as test objects.

Especially valuable are the compounds of Formula V in which R, standsfor benzyl or furfuryl which, when given to dogs at oral doses betweenabout 5 and 50 mg/kg/day, show outstanding hypotensive effects.

The pharmacologically active compounds of the invention can be used forexample, for the manufacture of pharmaceutical compositions, containingthem in conjunction or admixture with inorganic or organic, solid orliquid pharmaceutical excipients suitable for enteral or parenteraladministration. Suitable excipients are substances that do not reactwith the compounds of the invention, for example, water, gelatine,sugars, e. g. lactose, glucose or sucrose, starches, e. g. corn starchor arrowroot, stearic acid or salts thereof, e.g. magnesium or calciumstearate, talc, vegetable fats or oils, gums, alginic acid, benzylalcohols, glycols and other known excipients. The compositions may be,for example, in solid form as tablets, dragees or capsules, or in liquidform as solutions, suspensions or emulsions. They may be sterilizedand/or contain adjuvants, such as preserving, stabilizing, wetting oremulsifying agents, solution promoters, salts for regulating the osmoticpressure and/or buffers. They may further contain other therapeuticallyvaluable substances. These compositions are prepared by conventionalmethods; they usually contain about 0.1 to 75 percent, particularly 1 to50 percent of the active ingredient.

The following examples illustrate the invention and are not to beconstrued as being limitations thereon. Temperatures are given indegrees Centigrade and all parts wherever given are parts by weight.

EXAMPLE I Nl [-CIL-Callr,

separates; it is allowed to crystallize and is recrystallized fromaqueous ethanol.

Thestarting material is prepared as follows: 2.43 g of magnesiumturnings are placed in a flask, covered with 12 ml anhydrous diethylether, 2.5 g 4-br0mo3-chlorobenzotrifluoride and a small crystal ofiodine are added. The reaction mixture is heated gently until thereaction starts, then a solution of 23.5 g4-bromo-3-chloro-benzotrifluoride in 65 ml anhydrous di-ethyl ether isadded with stirring at a rate that the reaction continues vigorously.After the addition is completed, the reaction mixture is refluxed gentlyfor 30 minutes. Following the addition of 55 ml benzene, the mixture iscooled to -7 and dry carbon dioxide is bubbled in at such a rate thatthe temperature does not rise above --2 the reaction is completed whenthe temperature drops. Hereupon diluted sulfuric acid is added todecompose the magnesium salts and the reaction mixture is extracted withdiethyl ether. The combined extracts are shaken with three portions of25 percent aqueous sodium hydroxide, the combined alkaline extracts arewahsed with diethyl ether and acidified to yield the2-chloro-4-trifluoromethyl-benzoic acid.

10 g thereof are added to 50 g chlorosulfonic acid with stirring and themixture is heated to for 3 hours. After cooling the melt is carefullypoured over ice and water whereby the crude2-chloro-5-chlorosulfonyl-4-trifluoromethyl-benzoic acid precipitates incrystalline form. It is filtered off and added slowly to 50 mlconcentrated ammonia with cooling in an ice bath. After allowing tostand at room temperature for 3 hours the solution is heated it expellammonia. Hereupon it is filtered through charcoal and acidified. The2-chloro-5- sulfamyl-4-trifluoromethyl-benzoic acid precipitates incrystalline form; it is filtered off and recrystallized from aqueousethanol.

EXAMPLE 2 In the manner described in Example 1, the following compoundsare prepared from the equivalent amount of the corresponding startingmaterials:

2-cyclopentylmethylamino-5-sulfamyl-4-trifluoromethylbenzoic acid, 2-(3-cyclopentenyl-methylamino)-5-sulfamyl-4- trifluoromethyl-benzoic acid,2-(2-cyclopentyl-ethylamino)-5 -sulfamyl-4-trifluoromethyl-benzoic acid,2-cyclohexylmethylamino-5-sulfamyl-4-trifluoromethyl-benzoic acid, 2-(3- cyclohexenyl-methylamino)-5-sulfamyl-4-trifluoromethylbenzoic acid,2-cyclopropylmethylamino-5-sulfamyl-4- trifluoromethyl-benzoic acid,2-(4-hydroxymethyl-cyclohexylmethylamino)-5-sulfamyl-4-trifluoromethyl-benzoicacid, 2-(2-norbornanyl-methylamino)(-5-sulfamyl-4-trifluoromethylbenzoic acid,2-(2-norborn-S-enyl-methylamino)-5-sulfamyl- 4-trifluoromethyl-benzoicacid, 2-( S-methyl-furfurylamino )-5 -sulfamyl-4-trifluoromethyl-benzoicacid, 2-( 4-ethylthenylamino)-5-sulfamyl- 4-trifluoromethyl-benzoicacid, 2- 3,4-dimethyl-furfurylamino)-5-sulfamyl-4-trifluoromethylbenzoic acid,2-furfurylamino-5-sulfamyl-4-trifluoromethylbenzoic acid,2-thenylamino-5-sulfamyl-4-trifluoromethylbenzoic acid,2-(5-isoxazolyl-methylamino)-5-sulfamyl-4' trifluoromethyl-benzoic acid,2-(2-oxazolyl-methylamino)-5- sulfamyl-4-trifluoromethyl-benzoic acid,2-(2-thiazolylmethylamino)-5-sulfamyl-4-trifluoromethyl-benzoic acid, 2-(2-pyrrylmethylamino )-5-sulfamyl-4-trifluoromethyl-benzoic acid, 2-(2-benzimidazolyl-methylamino)-5-sulfamyl-4- trifluoromethyl-benzoicacid, 2-(1- or 2-indolyl-amino )-5- sulfamyl-4-trifluoromethyl-benzoicacid, 2-( 2-, 3- or 4-pyridyl-methylamino)-5-sulfamyl-4-trifluoromethyl-benzoic acid,2-(5-methyl-Z-pyridyl-methylamino)-5-sulfamyl-4- trifluoromethyl-benzoicacid, 2-[2-(2-pyridyl)-ethylamino]-5- sulfamyl-4-trifluoromethyl-benzoicacid, 2-dibenzylamino-5- sulfamyl-4-trifluoromethyl-benzoic acid,Z-(a-cyanobenzylamino)-5-sulfamyl-4-trifluoromethyl-benzoic acid, 2-l-phenyl-ethylamino)-5-sulfamyl-4-trifluoromethyl-benzoic acid, 2-(Z-phenyl-propylamino)-5-sulfamyl-4-trifluoromethylbenzoic acid, 2-[ 2-(2-hydroxy-ethoxy)-ethylamino ]-5- sulfamyl-4-trifluoromethyl-benzoicacid, 2-(4-dieth0xy-butylamino)-5-sulfamyl-4-trifluoromethyl-benzoicacid, 2-( 2- morpholino-ethylamino)-5-sulfamyl-4-trifluoromethyl-benzoicacid, 2-propargylamino-5-sulfamyl-4-trifluormethyl-benzoic acid,2-(4-sulfamyl-benzylamino)-5-sulfamyl-4- trifluoromethyl-benzoic acid,2-[2-(2,2,2-trifluoro-ethylmercapto)-ethylamino]-5-suflamyl-4-trifluoromethyl-benzoicacid and 2-carbamylmethylamino-5-sulfamyl-4- trifluoromethyl-benzoicacid.

unwwr EXAMPLE 3 To the solution of 3.1 g 2-chloro-5-sulfamyl-4-trifluoromethyl-benzoic acid in 6 ml I2-methoxy-ethanol, 5.2 mlfurfurylamine are added and the mixture refluxed for 4 hours. Aftercolling to room temperature 100 ml 2N- hydrochloric acid are added andthe aqueous layer is decanted off. The residue is triturated with waterwhereupon it solidifies. It is filtered off, dissolved in 50 ml 2Naqueous sodium hydroxide, the solution filtered, the filtrate extractedwith diethyl either and acidified with concentrated hydrochloric acid.The precipitate formed is filtered ofi and recrystallized from ethanolto yield the Z-furfurylamino--sulfamyl-4- trifluoromethyl-benzoic acidof the formula melting at 2 16 with decomposition.

The starting material is prepared as follows: 1n a 2 liter three-neckflask, fitted with stirrer, condenser and dropping funnel, the solutionof 40 g 3-amino-4-bromo-benzotrifluoride in 550 ml1,l,2,2-tetrachloroethane is placed and 13.2 ml chlorosulfonic acid in100 ml 1,l,2,2-tetrachloroethane are added dropwise while stirring andcooling. The mixture is heated to l30-140 for 4 hours, cooled to roomtemperature and filtered. The residue is washed with l,1,2,2-tetrachloroethane, dissolved in percent aqueous sodium carbonate and thesolution extracted with 1,1,2,2- tetrachloroethane. The aqueous layer isfiltered, the filtrate acidified with concentrated hydrochloric acidand, after cooling in an ice bath, filtered to yield the 5-bromo-2-trifluoromethyl-sulfamilic acid melting at 261-263 with decomposition.

37.6 g thereof are added portionwise to 128 ml chlorosulfonic acid whilestirring and the mixture is heated to about 113 for 3 hours. Aftercooling 55 ml thionylchloride are added and the mixture is heated for khour to about 100. It is cooled, poured onto ice, the residue formedfiltered off, washed with a small amount of water and added to 970 mlconcentrated aqueous ammonia. The mixture is heated on the steam bathfor l 1% hours, cooled in an ice bath and the precipitate formedfiltered off. It is washed with water and recrystallized from aqueousethanol to yield the 5-bromo-2- trifluoromethyl-sulfanilamide melting at200.5 to 201.5".

The mixture of 15.0 g thereof, 12.6 g cuprous cyanide and 105 mll-methyl-Z-pyrrolidone is kept at l53l55 under nitrogen for 18 hourswhile stirring. It is then cooled, poured into 600 ml water, the mixtureacidified with concentrated hydrochloric acid and filtered. The residueis washed with ethyl acetate and the filtrate extracted three times withethyl acetate. The extract is washed twice with water, filtered, driedand evaporated in vacuo. The residue is triturated withisopropanol-chloroform (1:1), filtered off, washed withisopropanol-chloro-form and recrystallized from aqueous ethanol to yieldthe 5-sulfamyl-4-trifluoromethyl-anthranilic acid nitrile melting at206-209.

0.5 g thereof are suspended in 10 ml 55 percent aqueous sulfuric acidand the mixture refluxed for /2 hour. It is poured onto ice, theprecipitate formed filtered off, dissolved in aqueous sodium carbonate,the solution filtered, acidified with concentrated hydrochloric acid,the precipitate formed filtered off and recrystallized from water toyield the 5-sulfamyl- 4-trifluoromethyl-anthrahilic acid melting at 258with decomposition.

2.07 g thereof are dissolved in ml water containing 0.7 g sodiumbicarbonate and 0.52 g sodium nitrite. The solution is added dropwise tothe stirred mixture of 2.6 ml concentrated hydrochloric acid and 10 mlwater, keeping the temperature at 5. The mixture is stirred for 15 hourand then added to a solution of cuprous chloride, which has beenprepared by combining the solution of 2.0 g copper sulfate pentahydrate,0.62 g sodium chloride in 7 ml water with that of 0.37 g sodiumbisulfite in 1 ml water, filtering the precipitate off, washing it withwater and adding it to the mixture of 4 ml concentrated hydrochloricacid and 4 ml water. The mixture is stirred at 55-65 for l A hours, thencooled, filtered, the residue washed with water, and dried to yield the2-chloro-5-sulfamyl- 4-tri-fluoromethyl-benzoic acid melting at 233-236with decomposition.

EXAMPLE 4 The solution of 1.5 g2-chloro-5-sulfamyl-4-trifluoromethylbenzoic acid in 3 ml2-methoxy-ethanol and 2.2 ml benzylamine is refluxed for 4 hours. Aftercooling to room temperature it is poured into 50 ml ZN-hydrochloricacid. The precipitate formed is filtered off, dissolved in about 30 ml2N aqueous sodium hydroxide, the solution extracted three times withdiethyl ether and the aqueous layer acidified with concentratedhydrochloric acid. The precipitate formed is filtered off andrecrystallized from aqueous ethanol to yield the 2-benzylamino-5-sulfamyl-4-trifluoromethyl-benzoic acid melting (afterdrying in a high vacuum at 70) at 240-240 with decomposition; it isidentical with the compound obtained according to Example 1.

EXAMPLE 5 To the solution of 1.9 g 2-chloro-5-methylsulfamyl-4-trifluoromethyl-benzoic acid in 6 ml Z-methoXy-ethanol, 3 mlfurfurylamine are added and the mixture refluxed for 4 hours undernitrogen. After cooling the mixture is poured into 75 ml 2N-hydrochloricacid, the precipitate formed filtered off, washed with water andrecrystallized twice from aqueous ethanol to yield the2-furfurylamino-5-methylsulfamyl-4- trifluoromethyl-benzoic acid of theformula (Ill; llNU S- melting at 201-202 with decomposition.

The starting material is prepared as follows: 26.0 g 5-bromo-2-trifluoromethyl-sulfanilic acid are added portionwise to 93 mlchlorosulfonic acid while stirring at room temperature. The mixture isthen heated to l13l 15 for 3 hours. After cooling, 39 ml thionylchloride are added and the mixture heated for k hour to about 95. It iscooled, poured onto ice while stirring, the residue formed filtered off,washed with water and added to ml of 25 percent aqueous methylaminewhile cooling in an ice bath. The mixture is stirred at room temperaturefor 2 k hours whereupon the solid is filtered off. It is washed withdiluted hydrochloric acid and water and recrystallized from aqueousethanol to yield the 5-bromo-Z-trifluoromethyl-N-methyl-sulfanilamidemelting at 155-156.

The mixture of 13.2 g thereof, 10.7 g cuprous cyanide and 100 ml1-methyl-2-pyrrolidone is stirred for 18 hours at under nitrogen. It iscooled, poured into 500 ml water, the mixture acidified withconcentrated hydrochloric acid and filtered. The residue is washed withwater and recrystallized from ethanol to yield the5-methylsulfamyl-4-trifluoromethylanthranilic acid nitrile melting at240-243.

4 g thereof are suspended in 80 ml 55 percent aqueous sulfuric acid andthe mixture refluxed for k hour. It is poured onto ice, the precipitateformed filtered off, dissolved in aqueous sodium carbonate, the solutionfiltered, acidified with concentrated hydrochloric acid, the precipitateformed filtered off and recrystallized from aqueous ethanol to yield the5-methylsulfamyl4-trifluoromethyl-anthranilic acid melting at 263 withdecomposition.

2.3 g thereof are dissolved in the mixture of 0.7 g sodium bicarbonate,0.55 g sodium nitrite and 45 ml water. This solution is added drop-wiseto the mixture of 3 ml concentrated hydrochloric acid and 10 ml waterduring 45 minutes while stirring at The mixture is stirred at foranother 45 minutes and then added drop-wise during minutes at roomtemperature to the solution of cuprous chloride, which has been preparedby combining the solution of 2.2 g copper sulfate pentahydrate and 0.7 gsodium chloride in 10 ml water with that of 0.4 g sodium bisulfite in 2ml water, filtering the precipitate off, washing it with water, andadding it to the mixture of 4.3 ml concentrated hydrochloric acid and4.3 ml water. The mixture is heated to 60 for l A hours, then cooled andextracted 3 times with ethyl acetate. The extract is dried, evaporatedin vacuo and the residue recrystallized from chloroform to yield the2-chloro-5-methylsulfamy1-4- trifluoromethyl-benzoic acid melting at208-212.

EXAMPLE 6 The mixture of 1.3 g 2-chloro-5-phenylsulfamyl-4-trifluoromethyl-benzoic acid, 1.4 ml furfurylamine and 6 ml 2-methoxy-ethanol is refluxed under nitrogen for 4 hours. lt is allowed tostand overnight at room temperature and poured into diluted hydrochloricacid. The precipitate formed is filtered off, washed with water anddissolved in 2N aqueous sodium hydroxide. The solution is extractedtwice with diethyl ether, the aqueous layer separated, acidified withhydrochloric acid and the precipitate formed filtered off. It is washedwith water, dried, dissolved in chloroform-formic acidisopropanol(9:1:2) and chromotographed on silica gel. The eluate obtained isevaporated and the residue recrystallized from chloroform-hexane toyield the Z-furfurylamino-S-phenylsulfamyl-4-trifluoromethyl-benzoicacid of the formula melting at 180-185 with decomposition.

The starting material is prepared as follows: The mixture of 49 g5-bromo-2-trifluoromethyl-sulfanilic acid and 175 ml chlorosulfonic acidis heated for 3 hours to 115. After cooling 75 ml thionyl chloride areadded and the mixture kept for A hour at 95. It is poured over ice, theprecipitate formed filtered off, washed with water, dissolved in 700 mlethyl acetate, the solution washed with water and dried. It is added tothe solution of 60 ml aniline in 100 ml ethyl acetate while stirring andstirring is continued for 4 hours at room temperature. After standingovernight, diluted hydrochloric acid is added, the organic layerseparated, washed with diluted hydrochloric acid, water, aqueous sodiumbicarbonate and dried. It is evaporated in vacuo and the residuerecrystallized from ethanol to yield the5-bromo-2-trifluoromethyl-sulfani1ic acid phenylamide melting at208-210.

The mixture of 17 g thereof, 11.6 g cuprous cyanide and 110 ml1-methyl-2-pyrrolidone is heated under nitrogen to 140 for 17 hourswhile stirring. After cooling, it is poured into 300 ml water, themixture acidified with hydrochloric acid and extracted with 500 ml ethylacetate. The extract is filtered, the filtrate washed with dilutedhydrochloric acid and water, dried and evaporated under reducedpressure. The residue is dissolved in hot ethanol, the solution treatedwith charcoal, diluted with water and kept in the cold. The crystalsseparated are collected and dried to yield the 5-phenylsulfamyl-4-trifluoromethyl-anthranilic acid nitrile melting at l85-l 88.

The mixture of 5 g thereof and 50 ml 35 percent aqueous sodium hydroxideis refluxed for 1 a hours. It is cooled,

diluted with water and acidified with sulfuric acid. The precipitateformed is filtered off, washed with water and recrystallized fromaqueous ethanol to yield the corresponding acid melting at 269 withdecomposition.

The solution of 2.0 g thereof in 60 ml glacial acetic acid is addeddropwise during k hour to the solution obtained from 0.42 g sodiumnitrite and 4 ml concentrated sulfuric acid at 101 5 while stirring. Themixture is stirred for 40 minutes at that temperature and then addedrapidly to the solution of cuprous chloride(prepared from 2.8 g cupricsulfate pentahydrate in 10 ml hot water, 0.8 g sodium chloride and 0.58g sodium bisulfite) in 5 ml concentrated hydrochloric acid and 5 mlwater at 40-50. The mixture is then heated to 65 for 1 1% hours, cooledand diluted with water. The precipitate formed is filtered off, washedwith water and recrystallized from aqueous ethanol to yield the2-chloro-5-phenylsu1famyl-4- trifluoromethyl-benzoic acid melting at 1831 84.

EXAMPLE 7 160,000 tablets each containing 100 mg of the activeingredient:

Formula: 2-furfurylamino-5-sulfamyl-4-trifluoro- The active ingredient,lactose, 2,5000 g of the corn starch, the sugar and colloidal cilica arepassed through a 16 mesh screen and mixed for 20 minutes. The remainingcorn starch is suspended in 1,000 ml cold water and the suspension addedto 4,000 ml boiling water. The mixed powders are granulated with thepaste obtained using additional water as required. The granulate ispassed through a 5 mesh screen, placed on trays and dried at 38 untilthe moisture content is between 2 and 3 percent. The granules are brokenon a mill, passed through a 16 mesh screen and treated with the stearicacid and calcium stearate both screened through a 20 mesh screen. Aftermixing for 20 minutes, the granulate is compressed into tablets using11/32 inch dies, standard concave punches, uppers bisected lowersmonogrammed. (The sieve sizes used are mesh per inch).

EXAMPLE 8 The mixture of 1.0 g Z-furfurylamino-5-sulfamyl-4-trifluoromethyl-benzoic acid N'-ben2ylhydrazide, 10 ml 2N- aqueoussodium hydroxide, 10 ml 2-methoxy-ethanol and 3 ml water, is refluxedunder nitrogen for 2 hours. 1t is cooled, poured into 20 mlZN-hydrochloric acid, the precipitate formed filtered ofi and dissolvedin 10 percent aqueous potassium carbonate. The solution is washed withethyl acetate, acidified with hydrochloric acid, the precipitate formedfiltered 01? and recrystallized from aqueous ethanol to yield the2-furfurylamino-5-sulfamyl-4-trifluoromethyl-benzoic acid melting at 216with decomposition; it is identical with the compound obtained accordingto Example 3.

The starting material is prepared as follows: The mixture of 6.1 g2-chloro-5sulfamyl-4-trifluoromethyl-benzoic acid, 50 ml1,2-dimethoxy-ethane and 8 ml thionyl chloride is refluxed for minutesand evaporated in vacuo. The residue is triturated with hexane andfiltered off to yield the 2-chloro-5- sulfamyll-trifluoromethyl-benzoicacid chloride.

6.0 g thereof are added in portions to the solution of 2.5 gbenzylhydrazine in m1 chloroform and 2.0 g triethylamine, during 10minutes while stirring. The mixture is stirred at room temperature for18 hours and evaporated in vacuo. The residue is dissolved in ethylacetate, the solution washed with water, dried and evaporated. Theresidue is purifled by chromatography on aluminum oxide to yield the 2-chloro-5-sulfamyl-4-trifluoromethyl-benzoic acid-N'-benzylhydrazide.

The mixture of 4.0 g thereof, 12 ml Z-methoxy-ethanol and 3.9 gfurfurylamine is refluxed for 3 hours, cooled and poured into 50 mlZN-hydrochloric acid. The precipitate formed is collected and dissolvedin ethylacetate. The solution is washed with diluted hydrochloric acidand water, dried and evaporated. The residue is triturated with diethylether and hexane, to yield the Z-furfurylamino-5-sulfamyl-4-trifluoromethyl-benzoic acid N'-benzylhydrazide, which is used as suchwithout further purification.

EXAMPLE 9 20,000 tablets each containing l mg of the active ingredient:

Formula: 2-chloro-5-sulfamyl-4-trilluoromethylbenzoic acidN'-benzylhydrazide 2,000.0 g Gelatin l50.0 8 Corn Starch (anhydrous)l,659.0 g Talcum 625.0 g Stearic Acid 66.0 g

Purified Water q.s.

Procedure:

The active ingredient and 726 g of the starch are passed through ascreen with 1 mm openings and mixed thoroughly. The gelatin is dissolvedin 2 liters water, the solution combined with a suspension of 308 gstarch in 400 ml cold water and the whole heated on the water bath untila paste is formed. It is combined with the sieved powders usingadditional water, if necessary. The granulate is passed through a screenwith 4 mm openings, dried at 49 and broken on a screen with 2 mmopenings of a comminuting machine, knives forward. To the granulate theremaining starch, talcum and stearic acid are added while mixing and themixture is compressed into tablets using standard concave punches doublescore.

We claim:

1. A compound of the formula in which R, is benzyl, l-phenylethyl,2-phenylethyl, furfuryl or thenyl, R is hydrogen and R is phenyl,benzyl, l-phenylethyl, 2-phenylethyl, furfuryl or thenyl, or an alkalimetal salt, an alkaline earth metal salt or the ammonium salt ofcarboxylic acid.

2. A compound as claimed in claim 1 and being the2-furfurylamino-S-phenylsulfamyl-4-trifluoromethyl-benzoic acid.

3. A compound having the formula in which R, is benzyl.

5. A compound as claimed in claim 3 and being the 2-chloro-S-phenyl-sulfamyl-4-trifluoromethylbenzoic acid.

6. A compound having the formula in which X is halogen and R ishydrogen, methyl, phenyl, benzyl, l-phenylethyl, 2-phenylethyl, furfurylor thenyl 7. A compound as claimed in claim 6, in which formula X isbromine and R is hydrogen, methyl or phenyl.

8. A compound having the formula in which R is hydrogen, methyl, phenyl,benzyl, l-phenylethyl, 2-phenylethyl, furfuryl or thenyl 9. A compoundas claimed in claim 8, in which formula R is hydrogen, methyl or phenyl.

v UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,678,039 I Dated July 18, 1 72.

Lincoln Harvey Werner et a1.

Inventor(s) It is certified vthat error appears in the above-identifiedpatent and that said Letters Patent are hereby' corrected as shownbelow:

On the Title page, the following should be added:

-- Assignee: Ciba Corporation, New York, N.Y.

Signed;- eno "sealed this 17gb day. of December 1974.

(SEAL) Attest:

McGOY M. GIBSON JR. C. MARSHALL DANN Attesting Officer Commissioner ofPatents.

Foam PO-IOSO (IO-69) v V 2 USCOMWDC and,

eovnmns'm PRINTING-OFFICE: 93 0

2. A compound as claimed in claim 1 and being the2-furfurylamino-5-phenylsulfamyl-4-trifluoromethyl-benzoic acid.
 3. Acompound having the formula in which X is fluoro, chloro or bromo and R3is phenyl, benzyl, 1-phenylethyl, 2-phenylethyl, furfuryl or thenyl, orthe amide, mono- or di-lower alkylamide, the hydrazide, N''-loweralkylhydrazide or N'',N''-di-lower alkylhydrazide, alkali metal salt,alkaline earth metal salt or the ammonium salt of the carboxylic acid.4. A compound having the formula in which R7 is benzyl.
 5. A compound asclaimed in claim 3 and being the2-chloro-5-phenyl-sulfamyl-4-trifluoromethylbenzoic acid.
 6. A compoundhaving the formula in which X is halogen and R3 is hydrogen, methyl,phenyl, benzyl, 1-phenylethyl, 2-phenylethyl, furfuryl or thenyl
 7. Acompound as claimed in claim 6, in which formula X is bromine and R3 ishydrogen, methyl or phenyl.
 8. A compound having the formula in which R3is hydrogen, methyl, phenyl, benzyl, 1-phenylethyl, 2-phenylethyl,furfuryl or thenyl
 9. A compound as claimed in claim 8, in which formulaR3 is hydrogen, methyl or phenyl.